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. Author manuscript; available in PMC: 2016 Feb 29.
Published in final edited form as: Curr Opin Behav Sci. 2015 Aug 1;4:128–135. doi: 10.1016/j.cobeha.2015.04.011

Using Intermediate Cognitive Endpoints to Facilitate Translational Research in Psychosis

Gary Gilmour 1, Francois Gastambide 1,*, Hugh M Marston 1, Mark E Walton 2
PMCID: PMC4770458  EMSID: EMS67340  PMID: 26937447

Abstract

Recent advances in the understanding of psychosis have uncovered potential for a paradigm shift in related drug discovery efforts. The study of psychosis is evolving from its origins in serendipity and empiricism to more formal, hypothesis driven accounts of the cognitive substrates underlying hallucinations and delusions. Recent evidence suggests that misattribution of salience and abnormal prediction error might underlie some forms of psychosis. If substantiated, such intermediate constructs could significantly facilitate translational research for drug discovery. Aberrant salience and prediction error can be assayed with simple tests of associative learning in both species, and a convincing back translation of effects, when combined with measures of neurotransmitter release and brain activity could for the first time allow robust, causal connections to be made between molecular mechanisms in rodents and symptoms in patients.

PSYCHOSIS: A TRANSDIAGNOSTIC TERM OF VARIABLE PRESENTATION

“Psychosis” presents contemporary researchers with a conundrum. While the term is in widespread usage, deeper analysis of its scientific application uncovers a bewildering complexity of semantic heterogeneity. Formal constructions of the concept of psychosis emerged in 19th century psychiatry [1], and presently have their most important homes as categorical definitions in DSM-V and ICD-10 [2,3]. While there is no single, simple definition, psychosis is generally understood as a clinical manifestation of an admixture of hallucinations (aberrant perceptions), delusions (false beliefs) and disorganised or catatonic behaviour, often causing great distress to those who experience it.

Psychotic experiences or “episodes” are essentially transdiagnostic. Although most frequently associated with conditions such as schizophrenia or bipolar disorder, they can be present in many other situations, such as Alzheimer’s disease, Parkinson’s disease, epilepsy, multiple sclerosis or even sleep disorders (Table 1). The quality, pattern and impact of the components of a psychotic episode can vary considerably between disease states; where for instance psychosis in schizophrenia most commonly presents as auditory hallucinations with complex, persecutory delusions, that in Alzheimer’s disease is more typically visual hallucinations with simpler, “misidentification”-type delusions [4,5]. Moreover, individual symptoms that characterise psychosis can be clearly observed, on occasion, in the general population [6]. The incidence of hallucinatory and delusional experiences is far greater than the reported rates for frank psychotic disorder, which has partly fuelled ongoing research regarding the validity of the notion of dichotomous presentation of psychosis (i.e. psychotic or not-psychotic) versus that of a “continuum” of psychosis [7]. As it stands, the utility of a term like psychosis for drug discovery, and the hypotheses that can be effectively tested on the basis of this concept, are somewhat limited.

Table 1. Prevalence rates of psychotic symptoms in various patient groups.

Disease/patient groups Prevalence rates
Bipolar disorder 76 % psychotic symptoms
Schizophrenia 73 % delusions, 59 % hallucinations
Bordeline personality disorder 50 % psychotic symptoms
Lewy body dementia 25 % delusions, 78 % hallucinations
Parkinson’s disease 5 % delusions, 30 % hallucinations
Alzheimer’s disease 10 % delusions, 21 % hallucinations
Delirium 43 % delusions, 86 % hallucinations
Narcolepsy 2 % delusions, 40 % hallucinations
Anxiety disorder 27 % psychotic symptoms
Post-traumatic stress disorder 12 % psychotic symptoms
Epilepsy 25 % psychotic symptoms
Multiple sclerosis 7 % delusions, 10 % hallucinations
Reproduced from Sommer and Kahn RS (2014)
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CLUES FROM SCHIZOPHRENIA RESEARCH

A number of the most important advances in the understanding of psychosis and its treatment have come from serendipitous findings in schizophrenia research. Discovery of the antipsychotic efficacy of chlorpromazine [8] and clozapine [9] in the 1950s and 1970s, respectively, paved the way for evolution of the so-called “dopamine hypothesis”. Various lines of research now converge to strengthen the validity of this hypothesis. Firstly, a large number of currently prescribed antipsychotics have dopamine D2 receptor antagonist effects, where strong relationships have been observed between D2 receptor occupancy and clinical efficacy [10,11]. Overactivation of D2 receptors is therefore likely to be one core chemical imbalance that can predispose to psychosis. The involvement of other receptors and pathways, such as the 5HT2A receptor, in the efficacy of atypical neuroleptics should not be overlooked, however [12]. Secondly, evidence from prodromal patient studies, where dopamine receptor tracer displacement is elevated in patients with ultra-high risk for psychosis or during first episode also supports the central role of overactive striatal dopamine neurotransmission in the emergence of psychotic states [13,14]. Finally, drugs such as amphetamine, methamphetamine and L-Dopa, which are known to increase dopamine release or activate dopamine receptors, have also been linked to the occurrence of psychotic episodes [15,16*,17]. Indeed, such molecules are often defined as a class of “psychotomimetic” agents. The dopamine hypothesis is complemented by the “glutamate hypothesis” [18*] which was also founded on initial serendipitous findings of pharmacologically induced psychosis, in this case following administration of phencyclidine and ketamine [19]. Both of these compounds have direct activity at NMDA receptors and do affect glutamatergic neurotransmission. From a drug discovery perspective, nearly all “antipsychotic” research has been based on empirical suppositions drawn from the dopamine and glutamate hypotheses, where researchers have hoped that novel agents can be identified if they share some of the properties that original antipsychotics possess in traditional behavioural pharmacological tests of preclinical efficacy, such as locomotor activity, prepulse inhibition or conditioned avoidance responding [20,21]. Prima facie, such assays appear to have little to do with psychosis as a human would experience it, and there can be an uncomfortable circularity to such research efforts.

Recent drives to increase the translational validity of psychiatric research in general may help to redefine the concept of psychosis. The need for improved translational validity has been borne from analysis of recent clinical failures in neuropsychiatric drug discovery, where lack of demonstration of target engagement and/or any measure of efficacy has been a worryingly pervasive concern [22]. Consensus is now growing that older, categorical and qualitative definitions of psychiatric disease need to be superseded by more mechanistically plausible, and preferably quantitative, domains of dimensional criteria as expounded by the recent Research Domains Criteria initiative [23*]. Fractionating psychosis into more mechanistic subcomponents that could be back-translated into rodents has great potential to increase construct validity of animal research. It may also provide novel efficacy biomarkers for human research allowing robust and unequivocal tests of hypotheses of cognitive enhancement, which in turn would also improve predictive validity.

TRANSLATING ABERRANT SALIENCE AND PREDICTION ERROR BETWEEN SPECIES

From a psychological viewpoint, evidence exists to suggest that patients experiencing delusions may have problems with associative learning processes, exhibiting biased reasoning (“jumping to conclusions”), attentional and attributional styles when ascribing meaning to events [24]. However, many such constructs drawn from human psychological literature are not necessarily easier to apply preclinically than the symptoms-based constructs of psychosis itself. A modern account of psychotic aetiology will therefore attempt to reconcile top-down psychological descriptions with bottom-up molecular hypotheses via the study of intermediate constructs. Two constructs in particular, aberrant salience and reward prediction error are gaining credence that they might represent useful cognitive intermediates. The proposed mechanistic chain would be that in an at-risk person dopaminergic dysregulation results one or both of misattribution of salience and inappropriate prediction errors, thereby leading to maladaptive learning [4,25,26**]. Maladaptive learning may in some cases alter a subject’s perception and appraisal of the external world, manifesting in a psychosis that has potential to be distressful and require treatment intervention. The processes of aberrant salience and distorted prediction error may be mutually reinforcing, a factor potentially contributing to the persistence of delusional beliefs in psychosis.

While an unequivocal demonstration of a hallucinatory or delusional event is beyond the realm of research in rodents, measures of salience and prediction error can be more readily employed and back-translated from clinical findings. The first of these constructs, aberrant salience, simply refers to an inappropriate assignment of potential importance, or value, (or the lack thereof) to stimuli, or events, in the environment [27]. The term ‘salience’ encompasses both low level stimulus-bound properties, such as loudness, but also the informational or motivational qualities that become attached to that object. While dopamine function is more commonly associated with reward and reinforcement, it is well established that it also signals the occurrence of salient novel events of potential significance [28-30]. These responses are typically short-lived, particularly when the event does not predict future reward or punishment and therefore has no consequences for the animal’s current state. Aberrant salience potentially represents a parsimonious construct through which hallucinatory experiences can emerge, while also having the potential to impact upon learning to cause delusional ideation. The second construct, reward prediction error (RPE), represents a core process by which new information (both positive and negative) is used to update predictions of future reward, a key component of associative learning and thereby cognition generally. Midbrain dopaminergic neuronal activity and dopamine release in the ventral striatum correlates closely with the RPE in temporal difference reinforcement learning models [31-33]. It has been suggested that delusions in psychosis might partly result from disrupted RPE signalling, which in turn allow inappropriate associations to form and then fail to be updated correctly [34-36].

Despite there being a number of unresolved questions and ongoing debates regarding the application and utility of these constructs, pragmatic starting points now exist to allow hypotheses related to drug discovery to be tested. Of primary importance is the ability to establish homologous assays of aberrant salience and prediction error between species. Both of these constructs are likely to be readily assessed via fairly simple associative learning paradigms, where for instance aberrant salience may be inferred from bias or abnormality in cue-reward associations during operant learning tasks, particularly in states of indefinite or ambiguous contingencies. Similarly, positive and negative prediction error signals can be readily generated with probabilistic cue discrimination tasks. A critical success factor here is that the final form of these rodent and human assays should be homologous (as far as possible), yet still have favourable practical attributes for electrochemical and imaging studies as described below.

With the establishment of homologous assays of salience and prediction error across species, it then becomes possible to consider the equivalence of underlying mechanisms and constructs between species. In this regard there are now several fMRI studies of reward-based tasks showing changes in RPE BOLD responses in patients suffering from psychotic illness in the vicinity of the midbrain dopamine cell bodies and regions that receive strong dopamine input such as the ventral striatum [4,37-39]. Until recently, it would have been difficult to realise the non-human equivalents of these studies as the restraint or anaesthesia required for BOLD imaging would have precluded the ability to meaningfully measure the relevant parameters simultaneously. However, the in vivo oxygen amperometry technique has been demonstrated to represent a viable means of bridging this gap. This technique allows real-time recording of brain tissue oxygen concentrations in several regions simultaneously while animals engage in behavioural tasks, including the types of reward-based learning and extinction paradigms that would be required to probe aberrant salience and prediction error [40*].

Finally, a means to perturb baseline responses will also be required to assess novel drug responses against. Psychotomimetic drugs, such as methamphetamine, may allow a translational means to provoke a homologous dopamine-based disruption of aberrant salience and prediction error between species. In this regard, it has demonstrated that a single dose of methamphetamine in healthy volunteers can induce mild psychotic symptoms whilst attenuating ventral striatal and prefrontal BOLD signals [41**]. Therefore, combining targeted pharmacological challenges [42] and electrochemical techniques, such as fast-scan cyclic voltammetry to measure real-time dopamine release [43], this brings forward the possibility of a seamless translational test of a pharmacological hypothesis at the level of a cognitive intermediate endpoint. The simultaneous application of behavioural assays, electrochemical techniques and imaging paradigms thereby offers a viable integrated cognitive approach by which to robustly test how aspects of the dopamine hypothesis relate to psychotic symptoms (Figure 1).

Figure 1. An integrated and translational endpoint approach for relating dopamine dysfunction to psychosis via the use of intermediate cognitive constructs.

Figure 1

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The top two panels illustrate the cognitive tests (top left) and neurochemical/imaging tools (top right) available in the translational toolkit. Probabilistic reward-based learning tasks such as the human monetary incentive delay task as well as rodent pavlovian and/or instrumental conditioning tasks, coupled with novel neurochemical and imaging techniques like fast-scan cyclic dopamine voltammetry and oxygen amperometry, allow for the assessment of salience and reward prediction error signals in both normal and disease states. The bottom panels depict a schematic representation of the proposed integrated cognitive endpoint approach to psychosis. (1) How does dopamine function modulate salience and reward prediction error? The use of fast-scan cyclic dopamine voltammetry in rodents during probabilistic reward-based learning tasks allows for the measurement of dopamine cell outputs in response to novel stimulus presentation (salience) but also to expected and unexpected reward delivery as well as omission or lack of expected reward (reward prediction error, RPE) (bottom left panel). (2) What are the oxygen correlates of dopamine salience and RPE signals? Analogous RPE-like signals can be recorded in both rodents and humans using oxygen amperometry and BOLD fMRI, respectively (middle panel). (3) Are these RPE-like oxygen correlates altered in psychotic patients and related disease models? Such patterns of activation in response to RPEs can be used to allow indirect investigation of disrupted dopamine function in patients with psychosis or normal subjects given a dose of D-amphetamine, as well as animal models of dopamine dysfunction (bottom right panel).

USING AN INTEGRATED COGNITIVE APPROACH FOR NOVEL ANTIPSYCHOTIC DRUG DISCOVERY

Although in its early stages, converging evidence suggests that applying models linking dopaminergic neuronal activity to learning and decision making can help shed light on how dysfunction in this system might underlie the development of psychotic symptoms.

Firstly, using such an integrated cognitive approach to determine whether there is a pathological threshold for the onset of full-blown psychosis could open novel approaches to pharmacotherapy. Indeed, many otherwise healthy individuals experience isolated psychotic events that do not lead to long-term psychosis [7]. It is also been reported that only a small subset of subjects with ultra-high risk for psychosis (i.e. 20-40%) are ever likely to proceed to a first episode of clinical psychosis [44]. Some studies already suggest that levels of dopamine and glutamate dysregulation may be sufficient to predict transition to psychosis [45]. If dopamine imaging studies can be related to dysregulation of salience and prediction error processes, then assays of these cognitive constructs may provide a very simple means to detect at-risk patients before first break. The plausibility of a preventive treatment intervention in psychosis ultimately depends on the future availability of such diagnostic power that is also relatively easy and cheap to administer. Future work should test whether such individuals exhibit a form of cognitive resilience, and/or the degree to which processes of aberrant salience and prediction error are disturbed. The finding that amphetamine administration can provoke measurable differences in striatal dopamine release in schizotypal subjects offers an intriguing experimental medicine model system for such research [46].

An integrated cognitive approach to psychosis may also help to determine the extent to which different forms of distressing psychotic experience share common mechanisms. A sensitised striatal dopaminergic system is likely a necessary substrate for the emergence of some forms of psychosis. However, it is not a sufficient explanatory account in isolation. For instance, a subset (i.e. 30-35%) of patients with schizophrenia show limited response to current dopamine-based antipsychotic medication [47,48]. Treatment resistance has been associated with other distinct neurochemical abnormalities, including prefrontal [49] and hippocampal glutamate levels [50]. Future work using the approaches described here to assess these different defined patient groups may lead researchers to unify the dopamine and glutamate hypotheses, where for instance an “upstream” dysfunction in hippocampal glutamate function may have a deleterious consequence on “downstream” striatal dopamine function [51*,52] to impact on psychotic symptoms.

The possibility of there being non-dopaminergic forms of psychosis, and/or that psychosis in disease states other than schizophrenia may be fundamentally mechanistically different is critical for the design of future clinical trials. Translational cognitive endpoints may eventually allow for stratification of patient populations based on defined, measurable constructs rather than on superficial symptomatology. As an example of the potential power of transdiagnosis, a recent imaging study found reduced cue-elicited reward anticipation signals in ventral striatum in patients diagnosed with schizophrenia, alcohol dependence or major depressive disorder [53**]. The converse may also be true, where studies of this sort may potentially start to tease apart diagnostic categories that appear to be related on the basis of face validity. A future clinical trial in psychosis may therefore seem to recruit patients from a broad and superficially disparate range of disease states, yet may yield greater efficacy through such targeting (Figure 2).

Figure 2. A transdiagnostic clinical trial approach in psychosis.

Figure 2

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In the context of a modern transdiagnostic approach to psychosis, patients might be recruited from a broad and disparate range of disease states, and screened for psychotic symptoms using psychotic symptom rating scales (1). Patients with a history of psychosis would then be further stratified to ensure that their symptoms were related to dysfunction in defined cognitive domains, where in the example provided patients could be screened for aberrant RPE and/or salience using BOLD fMRI coupled with cognitive paradigms such as the monetary incentive delay (MID) (2). The subset of psychotic patients with cognitive deficits in RPE and/or salience would finally be randomised for drug testing (3). Such an approach to clinical trial design may ultimately help to understand whether or not alterations in RPE and/or salience are predominant to schizophrenia or found across a broad range of diseases (4) and may also improve our understanding about the nature of hallucinations and delusions associated with cognitive deficits in RPE and/or salience mechanisms (5).

Finally, an integrated cognitive approach may help to better define more effective antipsychotics with utility in a broader range of psychoses. As described above, existing antipsychotics were not developed with a cognitive framework of psychosis in mind and have never been fully studied in this context. The framework offered by theories of aberrant salience and prediction error may even help to explain some of the potential side effects of D2 receptor antagonists. The sedation and social detachment that can be observed following treatment with typical antipsychotics in some patients might be explained in terms of an excessive dampening of salience. An integrated cognitive approach to psychosis may help to titrate effects on salience/prediction error and therefore better control the beneficial versus adverse effects of future therapies. Also, given the premise that cognitive dysfunction might underlie psychosis, it is important to consider how cognitive rehabilitation might be a necessary prerequisite or co-therapy for any drug treatment to be effective. Such combined clinical trials have been relatively scarce to date, and may possibly explain some recent failures of molecules, as seen particularly in Phase III.

Contemporary psychosis research is entering an exciting phase that ironically may lead to the term becoming obsolete or dramatically redefined. Many researchers are driven at present to better understand the causal relationship between changes in BOLD signal observed with fMRI and the underlying neurochemistry, and how both may formally relate to maladaptive cognition observed in psychosis (Table 2). It is here that the application of electrochemistry to measure real time fluctuations in both oxygen and dopamine signals in the striatum of animals performing reward-guided learning and decision making tasks, may be of particular use. There is hope that via cognitive constructs, such as aberrant salience and prediction error, basic molecular findings in animals can be related to human dysfunction associated with psychosis. This for the first time would then allow efficient use of quantitative, translational hypothesis based research to drive the development of much needed novel treatments.

Table 2. Outstanding issues.

  • UHR patient literature would suggest elevated dopamine synthesis capacity in dorsal associative striatum, yet altered BOLD responses to reward are usually reported in more ventral regions. Can these findings be unified?

  • Given the different timescales over which dopamine operates, from phasic bursts of activity across a few tens of milliseconds to slower tonic changes that may evolve across many minutes, can such temporal differences be related to specific aspects of salience or reward prediction error?

  • Can changes in dopamine electrochemistry be unequivocally related to changes in oxygen amperometry and/or BOLD signal?

  • If aberrant salience and prediction error are core substrates of psychosis, is there anything about the quality or magnitude of effect in these processes that can predict a transition to a full-blown, distressing psychotic state?

  • Should control subjects in clinical studies be assessed for incidence of sub-pathological psychotic behaviour, which may either reduce the discriminant power of the study or be an interesting population to study per se?

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Highlights.

  • Psychosis is a transdiagnostic complex of symptoms that may be more effectively fractionated

  • Aberrant salience and prediction error may provide intermediate cognitive constructs of psychosis

  • Dopamine and glutamate hypotheses may relate to and explain dysfunction in salience and prediction error processes

  • Translational technologies and endpoints can now be developed to reconcile findings across species

Acknowledgments

Financial disclosure: This work was supported by Eli Lilly and Company through the Lilly Research Awards Program (LRAP). GG, FG, HMM declare being employees of Eli Lilly & Co Ltd. MEW is also supported by a Wellcome Trust Research Career Development Fellowship (090051MA).

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